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Nano and Micro Technologies

Nano and Micro Technologies - Poster Session D

Poster Y19 - A traumatic brain injury (TBI)-on-a-chip model for biomarker discovery and therapeutics development

Friday, October 25, 2024
3:30 PM – 4:30 PM EST
Location: Exhibit Hall E, F & G

Introduction:  Traumatic brain injury (TBI), caused by mechanical forces as a result of impact, penetration, or rapid acceleration/deceleration, is a major cause of death and disability worldwide. TBI survivors may experience movement disorders, memory loss, and cognitive deficits, which cause a heavy socio-economic burden. Progressive neurodegenerative proteinopathies such as Parkinson's and Alzheimer's diseases are the most significant long-term sequelae of TBI. Although systematic reviews have found that TBI is associated with a 63%-96% increased risk of all-cause dementia, molecular mechanisms that underlie this risk are mainly unidentified. The neurovascular unit (NVU) is a functional unit composed of neurons, astrocytes, microglia, specialized endothelial cells (blood-brain barrier; BBB), mural cells, and the basement membrane. Studies have shown that TBI can cause BBB damage and prolonged structural and functional abnormalities of the NVU. Thus, studying biological processes critical in NVU dysfunction following injury might help find better TBI biomarkers, develop TBI therapies, and understand TBI-induced neurodegenerative disease pathways. In this study, we aimed to i) develop an NVU-on-a-chip device that emulates the physiological complexity of the human NVU in ways that have not been possible using conventional techniques and ii) explore the potential of this model to investigate biological responses to the injury and understand underlying molecular mechanisms. Importantly, this model will enable us to investigate the role of each cellular component of the human NVU in brain injury.

Materials and

Methods:  We use an NVU-on-a-chip model based on the co-culture of brain microvascular endothelial cells (BMVECs), pericytes, astrocytes, and neurons of human origin. In this microphysiological system, endothelial cells, pericytes, and astrocytes are embedded in a fibrin hydrogel scaffold to form perfusable, interconnected capillary networks mimicking BBB. Astrocytes are positioned between neurons and capillary BMVECs and communicate with these cells through their foot processes. To mimic this structure, neurons are cultured in the top wells of our NVU-on-a-chip devices. After establishing the NVU-on-a-chip model (used as the “healthy control” in our TBI studies), we focused on developing the TBI-on-a-chip model, which uses uniaxial stretching to mimic concussion in vitro.

Results, Conclusions, and Discussions: Our data showed that uniaxial stretching (15% strain) dramatically decreases pericyte coverage and tight junction expression. In addition, under 15% strain conditions, apoptosis and necrosis (Caspase 3/7 activity and lactate dehydrogenase (LDH) release), proinflammatory cytokine release, and oxidative stress increase compared to the control NVU-on-a-chip group. We also showed that the changes in the cells upon uniaxial stretching are strain-dependent. Studying transcriptomic differences in the TBI-on-a-chip models by single-cell sequencing will advance our molecular understanding of the changes following brain injury and contribute to discovering new molecular signatures of TBI. To our knowledge, these types of in-depth studies have not been reported in the literature. In conclusion, our 3D, micro-engineered in vitro NVU model allows us to study NVU changes in brain injuries and molecular mechanisms critical in the development of neurodegenerative diseases.

Acknowledgements (Optional):